Deconstructing an opioid receptor could pave the way to safer painkillers

Most opioids bind to several cell surface receptors, which allows them to treat severe pain but also causes myriad side effects.

University of North Carolina scientists unraveled the structure of a cell surface opioid receptor and created a drug compound targeting it, paving the way for the development of more selective painkillers that relieve pain without causing side effects.

The UNC team looked at the crystal structure of the kappa opioid receptor (KOR) when it is bound to a morphine derivative. This allowed them to identify which parts of the receptor are important for binding to druglike compounds. They then designed a compound that bound to KORs “extremely selectively” in cell cultures, according to a press release. Their work appears in the journal Cell.

Most opioids bind to multiple receptors, which is one of the main reasons they cause side effects such as nausea and constipation, as well as dependence, overdose and death, the UNC team said. Activating a single receptor, the KOR, could head off these side effects.

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"To create better opioids, we need to know the structure of their receptors," said senior author Bryan Roth, M.D., Ph.D., a professor of protein therapeutics and translational proteomics at UNC Chapel Hill. "Until recently, this was impossible. But now we know the structure of the activated kappa opioid receptor. And we showed we can actually use the structure to make a drug-like compound with better properties than current opioids."

Other approaches to tackle the drug dependency behind the opioid epidemic include drugs that act on the mu opioid receptor. Nektar Therapeutics’ candidate posted positive phase 3 results, while Mebias has a pair of mu-opioid agonists that show preclinical promise. Trevena has seen fit to slash a third of its staff, abandon its heart failure drug and halt early-stage R&D so it can throw all of its weight behind its lead pain asset, Olinvo.

A team at Indiana University came up with an opioid alternative that works like cannabis, amplifying the brain’s ability to produce painkillers, while the NIH and the Walter Reed Army Institute of Research developed a vaccine that prevents heroin from crossing the blood-brain barrier. They hope that the jab, which also produces antibodies against other opioids, such as hydrocodone and oxycodone, can serve as a bridge to recovery for people trying to beat their addiction.

While the KOR approach is attractive, it is not without risk. Drugs that activate this receptor can trigger other side effects, including hallucinations and dysphoria. That's where the newly understood KOR structure comes in.

"It's now possible to design new drugs based on the findings on this active KOR structure and tweak them to only have the desired pain relief effects,” said first author Tao Che, Ph.D., a postdoctoral fellow in Roth’s lab.

The UNC team is now planning to work on more KOR-targeted compounds and test them in animal models.